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To re-evaluate whether phosphate-deprivation alters serum 1,25-(OH)2-D concentrations in men, we measured serum 1,25-(OH)2-D levels in seven healthy men while they ate constant diets providing 52.2 +/- 4.3 sd mmoles PO4/day for 12 days and then while they ate a diet providing 29.4 +/- 6.0 mmoles PO4/day and also were given Al(OH)3 for 18 days. Serum PO4 levels fell only transiently. Net intestinal PO4 absorption became indistinguishable from zero but, because of renal PO4 conservation, PO4 balances did not change. Nevertheless, serum 1,25-(OH)2-D concentrations increased from 80 +/- 21 pM during control to 104 +/- 26 pM; during PO4 deprivation; P less than 0.01. Net intestinal calcium (Ca) absorption tended to rise during PO4 deprivation, the individual increments being correlated to the increments in serum 1,25-(OH)2-D concentrations (r = 0.78; P less than 0.05). Urinary Ca excretion rose; P less than 0.001, the increments exceeding the increments in net intestinal Ca absorption so that Ca balances became more negative; P less than 0.001. Urinary hydroxyproline excretion did not change. Thus, as in women and animals, PO4 deprivation appears to cause enhanced net bone resorption apparently by reducing bone formation.
Much has been learned about the formation of the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3. Information concerning its formation and catabolism has allowed a clear understanding of factors involved in the maintenance of plasma concentrations of the hormone. The effects of 1,25-dihydroxyvitamin D3 on calcium transporting cells in the intestine are marked and well defined. The tissue (intestinal tissue) is easily isolated and manipulated and hence, this is an ideal tissue in which to examine the mechanism of divalent cation transport. The mechanism by which 1,25-dihydroxyvitamin D3 brings about this effect should help in understanding sterol hormone action.
Hypercalcemia is associated with impaired urinary concentrating ability. To explore the mechanism(s) by which hypercalcemia impairs chloride transport in the loop of Henle, we carried out in vivo microperfusion of the loop segment in Sprague-Dawley rats rendered acutely hypercalcemic (12.1 +/- 0.1 mg/dliter) by calcium gluconate infusion. Control rats were infused with sodium gluconate and had normal plasma calcium (8.0 +/- 0.2 mg/dliter). Compared to control, fractional chloride reabsorption was decreased (61 +/- 4 to 50 +/- 3%; P less than 0.05) and early distal chloride increased 74 +/- 6 to 98 +/- 3 mEq/liter (P less than 0.001) in hypercalcemia. During hypercalcemia, infusion of verapamil failed to increase fractional chloride reabsorption (49 +/- 4%; P less than 0.05) or decrease early distal chloride (95 +/- 2; P less than 0.05) toward control values. Similarly, indomethacin did not improve fractional chloride reabsorption (48 +/- 4%; P less than 0.05) or distal chloride concentration (93 +/- 7; P less than 0.05). In control rats infused with Ringers HCO3, the addition of calcium 8.0 mEq/liter to the perfusate increased early distal calcium (9.22 to 3.11 mEq/liter) but was associated with no change in fractional chloride reabsorption (-6 +/- 6%) and a slight decrease in early distal chloride (-9 +/- 3 mEq/liter; P less than 0.05). These data are consistent with the hypothesis that an elevated plasma, not luminal calcium, concentration impairs chloride reabsorption in the loop segment, primarily the ADH-stimulated component. This may have an important role in the urinary concentrating defect of hypercalcemia.
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Because of the recently observed augmentation of medullary hypoxic injury by calcium in isolated perfused rat kidneys (Kidney Int 34:186-194, 1988), renal morphology of chronic, prolonged hypercalcemia was investigated in vivo. Rats were treated with repeated injections of vitamin D2 (400,000 units/week) for two to eight weeks. Chronic elevation of plasma calcium from 2.1 to 2.8 mmol/liter (P less than 0.001) was associated by a fall in maximal urine osmolality with no change in glomerular filtration rate. The most significant morphological alterations occurred in the inner stripe of the outer medulla; these changes were characterized by a sequence of active injury with subsequent destruction and atrophy of the medullary thick ascending limbs, fibroblastic and lymphocytic infiltration, and secondary dilatation of collecting ducts. Similar changes occurred in the medullary rays. These alterations were accompanied by increased renal prostanoid production and a predisposition to acute kidney failure from indomethacin. Because of its selective occurrence in zones of poorest oxygen supply, this inner stripe injury may derive from vulnerability to hypoxia and may play a role in some chronic nephropathies.
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Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer. Approximately 30% of patients with localised prostate cancer relapse at the irradiated site. Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common. Thus, the search for biological response modifiers that could potentiate the therapeutic effects of radiation and limit the occurrence of serious side effects is an important task in prostate cancer therapy. 1alpha,25-Dihydroxyvitamin D(3) (calcitriol), the active metabolite of vitamin D, and its analogues are under investigation for the treatment of several malignancies including prostate cancer. Here, we report that 1alpha,25-dihydroxyvitamin D(3) and its less calcaemic analogue 19-nor-1alpha,25-(OH)(2)D(2) (Zemplar) act synergistically with IR to inhibit the growth of the human prostate cancer cells in vitro. 1alpha,25-dihydroxyvitamin D(3) potentiated IR-induced apoptosis of LNCaP cells, and nanomolar doses of 1alpha,25-dihydroxyvitamin D(3) and 19-nor-1alpha,25-(OH)(2)D(2) showed synergistic inhibition of growth of LNCaP cells at radiobiologically relevant doses of IR (1-2 Gy). At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism. The synergistic effect at radiobiologically relevant doses of radiation suggests that a combination of 1alpha,25-dihydroxyvitamin D(3) or 19-nor-1alpha,25-(OH)(2)D(2) with IR could permit a reduction in the dose of radiation given clinically and thus potentially reduce treatment-related morbidity.
OBJECTIVES: To study the effect of vitamin D supplementation and the impact of summer season on serum 25-hydroxyvitamin D (S-25(OH)D) in Finnish 9-15-y-old girls. DESIGN: Three-year follow-up study with vitamin D(2) supplementation using D(2) 10 microg daily from October to January for the first and from October to February for the second winter as well as 20 microg daily from October to March for the third winter. SETTING: Paavo Nurmi Centre, University of Turku, Turku, Finland. SUBJECTS: A total of 171 female volunteers aged 9-15 y. METHODS: Vitamin D and calcium intakes were estimated by a semi-quantitative food frequency questionnaire (FFQ). S-25(OH)D was measured by radioimmunoassay. RESULTS: The median daily dietary intakes of vitamin D and calcium were 3.8 microg (interquartile range (IQR) 2.7-5.0) and 1451 mg (IQR 1196-1812), respectively, over 3 y. The prevalence of severe hypovitaminosis D (S-25(OH)D<20 nmol/l) was 14% and of moderate hypovitaminosis D (20 nmol/l < or = S-25(OH)D < or = 37.5 nmol/l) 75% at baseline in winter. None of the participants had severe hypovitaminosis D in summer. The effect of 10 microg of D(2) daily was insufficient to raise S-25(OH)D from baseline. The daily supplementation of 20 microg of D(2) increased S-25(OH)D significantly in wintertime compared with the non-supplement users (to 45.5 vs 31.8 nmol/l; P<0.001). None of the subjects with vitamin D(2) supplementation approximately 20 microg daily had severe hypovitaminosis D; however, 38% of those participants had moderate hypovitaminosis D at 36 months. Sun exposure in summer raised mean S-25(OH)D to 62.0 nmol/l. Both the daily supplementation of approximately 20 microg of D(2) and summer sunlight exposure had more effect on those who had severe hypovitaminosis than those who had a normal vitamin D status (increase of 24.2 vs 0.9 nmol/l (P<0.001), and 38.8 vs 18.2 nmol/l (P<0.001), respectively). CONCLUSION: Vitamin D supplementation daily with 20 microg is needed to prevent hypovitaminosis D in peripubertal Finnish girls in winter. Sunlight exposure in summer is more effective than approximately 20 microg of D(2) supplementation daily in winter to raise S-25(OH)D. Both the daily supplementation with 20 microg of D(2) and summertime sunlight exposure had more effect on those who had severe hypovitaminosis D than those who had a normal vitamin D status. SPONSORSHIP: Supported by the Yrjö Jahnsson Foundation and the Medical Research Foundation of the Turku University Central Hospital.
OBJECTIVE: Assessment of the effectiveness and safety of high daily 125 microg (5,000 IU) or 250 microg (10,000IU) doses of vitamin D(2) during 3 months, in rapidly obtaining adequate 25 hydroxyvitamin D (25OHD) levels. DESIGN: Longitudinal study. SUBJECTS: Postmenopausal osteopenic/osteoporotic women (n = 38) were studied during winter and spring. Median age (25-75th percentile) was 61.5 (57.00-66.25) years, and mean bone mineral density (BMD) was 0.902 (0.800-1.042)g/cm(2). Subjects were randomly divided into three groups: control group (n=13): no vitamin D(2), 125 mug/day (n=13) and 250 microg/day (n=12) of vitamin D(2) groups, all receiving 500 mg calcium/day. Serum calcium, phosphate, bone alkaline phosphatase (BAP), C-telopeptide (CTX), 25OHD, mid-molecule parathyroid hormone (mmPTH), daily urinary calcium and creatinine excretion were determined at baseline and monthly. RESULTS: For all subjects (n=38), the median baseline 25 hydroxyvitamin D (25OHD) level was 36.25 (27.5-48.12) nmol/l. After 3 months, 8% of the patients in the control group, 50% in the 125 microg/day group and 75% in the 250 microg/day group had 25OHD values above 85 nmol/l (34 ng/ml). Considering both vitamin D(2) groups together, mmPTH and BAP levels diminished significantly after 3 months (P<0.02), unlike those of CTX. Serum calcium remained within normal range during the follow-up. CONCLUSIONS: The oral dose of vitamin D(2) required to rapidly achieve adequate levels of 25OHD is seemingly much higher than the usual recommended vitamin D(3) dose (20 mug/day). During 3 months, 250 microg/day of vitamin D(2) most effectively raised 25OHD levels to 85 nmol/l in 75% of the postmenopausal osteopenic/osteoporotic women treated.
Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.
Intravenous vitamin D is standard therapy for secondary hyperparathyroidism in hemodialysis (HD) patients. In for-profit dialysis clinics, mortality was higher for patients on calcitriol compared to paricalcitol. Doxercalciferol, a second vitamin D2 analog, is currently available. We assessed mortality associated with each vitamin D analog and with lack of vitamin D therapy in patients who began HD at Dialysis Clinic Inc. (DCI), a not-for-profit dialysis provider. During the 1999-2004 study period we studied 7731 patients (calcitriol: n=3212; paricalcitol: n=2087; doxercalciferol: n=2432). Median follow-up was 37 weeks. Mortality rates (deaths/100 patient-years) were identical in patients on doxercalciferol (15.4, 95% confidence interval (13.6-17.1)) and paricalcitol (15.3 (13.6-16.9)) and higher in patients on calcitriol (19.6 (18.2-21.1)) (P<0.0001). In all models mortality was similar for paricalcitol versus doxercalciferol (hazard ratios=1.0). In unadjusted models, mortality was lower in patients on doxercalciferol (0.80 (0.66, 0.96)) and paricalcitol (0.79 (0.68, 0.92)) versus calcitriol (P<0.05). In adjusted models, this difference was not statistically significant. In all models mortality was higher for patients who did not receive vitamin D versus those who did (1.2 (1.1-1.3)). Mortality in doxercalciferol- and paricalcitol-treated patients was virtually identical. Differences in survival between vitamin D2 and D3 may be smaller than previously reported.
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